Several strategies have recently been pursued to improve EOC therapy by delivering chemotherapeutic agents in a targeted fashion. These include the attachment of highly potent toxins to antibodies, forming antibody-drug conjugates (ADCs), and, the incorporation of existing small molecule chemotherapies within nanoparticles (NPs). There are currently several ADCs in last stage clinical development for “platinum resistant” EOC (e.g. Mirvetuximab soravtansine (IMGN853); ImmunoGen Inc., Waltham, Mass.). Most of these agents bind 1-4 toxin molecules per antibody, are critically reliant on the properties of their drug-linker, and can suffer from suboptimal tradeoffs between efficacy and therapeutic index; dissociation of the toxin payload is necessary for antitumor activity but the prolonged circulation times of ADCs may lead to premature drug release, which results in persistent and sometimes significant side effects. Similarly, the first-generation of clinically tested NPs have generally failed to improve the therapeutic efficacy of their associated agents. They have typically incorporated drugs with tolerable toxicity profiles such as doxorubicin (e.g. DOXIL® (doxorubicin HCl liposome injection); Johnson & Johnson) and paclitaxel (e.g. Abraxane® (paclitaxel protein-bound; Celgene), displaying modest activity against multiple cancer cell types (i.e. IC50s in the tens to hundreds of nanomolar range); additionally, they have generally relied on drug encapsulation as opposed to chemical conjugation. As a result, these NPs have displayed continuous drug release during their intravascular circulation, which has led to persistent off-target side effects with only mild increases in antitumor efficacy.
The development of novel agents and delivery methods with increased antitumor efficacy and limited toxicity is, thus, a critical unmet need.